Influenza virus infection of the lungs causes a contagious acute respiratory disease that may result in severe complications such as pneumonia. Despite the active vaccine program, influenza virus remains a major global human pathogen causing annual epidemic and occasional pandemics with morbidity and mortality. Resistance to all available anti-flu drugs has been identified in influenza virus isolates, highlighting the need and urgency to develop novel anti-flu therapeutics. Host signaling pathways and host factors that are involved in the flu life cycle represent potential anti-viral targets, but the poor understanding of their functions and mechanisms in viral replication is a major barrier for the development of appropriate interventions. We have preliminary data to suggest that host nerve growth factor (NGF) receptor TrkA signaling plays important roles in the influenza viral replication at the step of viral RNA synthesis. TrkA is a member of neurotrophin receptor tyrosine kinases that also include TrkB and TrkC. It has been shown that neurotrophins and Trk receptors are expressed in many non-neuronal tissues including human lungs, but their pathophysiological roles in lungs remain largely unknown and their potential functions in the replication of respiratory viral pathogens have never been investigated. We hypothesize that host TrkA signaling is activated by influenza viral infection and, in a positive feedback loop, facilitates influenza viral replication by enhancing viral RNA synthesis. We propose to validate this novel hypothesis by determining the specific role of TrkA, B, and C in flu viral replication and RNA synthesis (Aim 1) and the mechanism of TrkA signaling involved in flu viral RNA synthesis (Aim 2). This exploratory study will evaluate a complete novel concept on the importance of host TrkA signaling in the influenza virus infection, provide the conceptual and factual basis for a subsequent full scale research effort on the mechanistic characterization of host signaling in the flu viral RNA synthesis, and potentially lead to the development of novel anti-viral therapeutics to treat this infectious lung disease. In a broader sense, it will shed important insights into an unknown area of how the Trk signaling in the lungs affect the replication of respiratory pathogens that may lead to novel broad-spectrum therapeutic measures against a class of infectious respiratory diseases. PUBLIC HEALTH RELEVANCE: Influenza is a contagious acute respiratory disease caused by influenza virus infection of the lungs, which may lead to severe complications such as pneumonia. Novel anti-flu drugs are urgently required as the current ones are quickly becoming out-of-date due to emergence of drug-resistant viral variants. We have preliminary data to suggest a novel functional role of host TrkA signaling in the influenza viral replication and viral RNA synthesis. We propose to evaluate and mechanistically characterize the role of host TrkA signaling pathways in the influenza viral RNA synthesis. These studies may lead to the identification of novel drugs against a class of infectious respiratory diseases.